Ww" protecting Wee SSMIKO NN infection can also prevent cancer In September 2008 the UK started a new vaccination programme designed to cut the risk of cervical cancer in women caused by the human papilloma virus (HPV). So how does vaccination work, and how might we improve vaccines in the future? Key words Vaccine HEV Dendrite calls Antibody Lymphocytes: tr immune system is a powerful network of interacting cells and molecules with a specific function to protect us from infection. This is no small task when we consider the huge range of pathogens to which we are exposed, From viruses to bacteria, fungi and protozoa, we live in a hostile environment, so it's not too surprising that we have evolved a complex immune system to deal with these various threats. Immunologists like to split the immune system into two main branches. Innate immunity includes physical barriers 10 infection, such as skin and mucus ‘membranes. It also includes key phagocytic cells such as neutrophils and macrophages, which circulate in the blood. Adaptive immunity requires a pool of specialised antigen-presenting cells and lymphocytes also found in the blood. The most important antigen: presenting cells are dendritic cells, which are distrib uted in most tissues of your body, especially those at risk from infection. Lymphocytes are divided into different types. Some lymphocytes, called T cells, can, directly kill virus-infected cells. Others, called B cells, produce antibodies that will recognise and bind to the infecting organism, Sigal inthe last few years thas become clear that molecules called pattem recognition recepos, expressed by cells ofboth the Innate andthe adap tive immune systems, are eral to generating sty cules that are typical of invading organisms, suchas cel surface macomolecles,RNA and bacterial DNA. These molecules are sometimes called ‘danger’ signal because they worn the immune systern of something that poses a treat To understand vaccination fully we need to know how a normal immune response is made to an invading pathogen. Pathogens that enter the body through the skin, the lungs or the gut will encounter phagocytic and dendritic cells, Interaction with the pattern recognition receptots on the surface of the dendritic cells induces activation and causes the dendritic cells to migrate to 2 local Iymph node, several hundred of which occur throughout the body. The dendritic cells also digest and chop up the pathogen into small fragments. Qace in a Iymph node, dendritic cells display the dig QM BioLoGicaL sciENees REweWBacter: fragments of the pathogen to specialised lymphocytes. The lymphocytes then muliply into populations of cells that either directly kill infected cells or are helper cells. ‘These helper cells assist further specialised lymphocytes to produce antibodies that bind to pathogens (see Figure 1), The activated lymphocytes are released into the blood to seck out and destroy the infection, Finally, a key feature of the adaptive response, which Js not present inthe innate response, isthe development of ‘memory’. A small population of pathogen-specific lymphocytes can survive in your body for many years. Ifand when you next encounter that same pathogen, or a close relative of it, these cells will multiply rapidly provide a strong protective immune response. It is capacity for memory that we rely on when we What makes a vaccine a vaccine? Vaccination has been one of the most effective health: care strategies ever developed, It has prevented millions oof deaths and severe complications from diseases such as smallpox, polio and measles, The key fact 10 understand is that vaccines work by producing the same immune response that we would make to a real invading pathogen, but without exposing us to the full risks of that pathogen. A variety of different types of vaccine have been developed in an attempt to achieve this protection. Attenuated vaccines contain live pathogens that have been treated or weakened so that they will not cause full disease. Because they are live, and. can undergo some of the replicative stages that -n within the cells of the body, they are usually WWE sos oh mmune stm A pret! SEPTEMBER 2009 2 So—o—s Cytotoxic T cell Direct kiling of infected cells Figure 1 How pathogens stimulate an immune response. From lft to right infectious agents gain access to your body; components ofthe pathogens are often recognised by pattern recognition receptors on dendritic cells, which can ingest an d degrade them, then, ina mph noe, the dendritic vlls use fragments ofthe pathogen to stimulate Iymphocytes tat can crety klnfected cals, o help other iymphortes to produce antibodies, disadvantage of this type of vaccine is the small of reversion of the weakened pathogen to a disease- pathogen. Attenuated vaccines can also pose a risk 10 people who have weakened immune systems. ‘An example of an attenuated vaccine tht is still used In the UK is the MMR (measles, mumps and rubella) vaccine, Killed vaccines cannot cause infection and so are safer than live attenuated vaccines but they are often less potent stimulators of the immune system because they fail to infect cells in your body. Flu vaccines fall into this category. Because the flu virus can undergo dramatic changes in its DNA that alter its immunogenic proteins (the bits that are recognised by the immune system), new batches of virus are prepared every year using predictions of the strains most likely to cause ‘outbreaks. ‘Subunit vaccines comprise one or several isolated parts of a pathogen. In the case of tetanus toxoid vaccine, the idea is not to protect you from infection with the virus but to prevent the life-threatening effects of the toxin that is produced during infection, The abllity to produce recombinant proteins (see BI0LOG- Icat Scunces RevEW, Vol. 19, No. 1, pp. 24-28) has also allowed the generation of recombinant vaccines, where a single protein from a pathogen, or small synthetic peptides from the immunogenic segment of a pathogen protein, is used. Purified extracts of bacterialFurther reading Miller, J. (2007) ‘Training killers: dendritic cells’ Biowosical Sciences Review, Vol, 19, No. 4, pp. 117. For mote details on the HPV vaccine and infectious diseases in the Uk: (cervical cancer and HPV) (ine Health Protection Agency) cell capsules can also be used as vaccines. An example of such a polysaccharide vaccine js the pneumo- coceal conjugate vaccine, which contains components of seven of the most common pneumococcal bacteria There are differences in the strength of response that each type of vaccine generates from the immune system. To counter this problem, vaccines often indude adjuvants. The purpose of an adjuvant is to act as a strong immune stimulus, often by activating the immune system through the pattern recognition recep- tors as discussed earlier, A new dawn: vical car We now have the exciting opportunity to make a huge difference to a widespread female health problem vaccinating TERMS exiainea © ‘Adjuvant An ager that is co-injected with the vaccine to enhance the immune response, Polysaccharide vaccine A vaccine that includes compo- nents of bacterial cell walls. Recombinant vaccine A vaccine where genetic eng neering has been used to isolate a small segment of 2 pathogen. ‘Subunit vaccine A vaccine where an isoisted part or parts ofthe pathogen are used, Tetanus toxoid A vaccine thal includes an inactivated form of the toxin that normally affects the central nervous system, through the use of vaccination, Around 3000 women in the UK ate dagnosed with cervical cancer every yeat, with about 1500 deaths annually. Worldwide the problem increases to around 5000000 new @)) each yeat. It has been known for a long time Mat cervical cancer can be cased by infection with human papilloma vias (HPV, see Bozocicn, SceNces Revie, Vol. 12, No.2, pp. 8-10) THPV isa small virus with a DNA genome that is cnly 8000 base pairs long, and it contains only ten genes. Ie is nota rare vis by any means — eight out BloLosteaL scieNces Reviewoften of us, male and female, have met the virus at point in our lives. The vast majority of people, MMWever, will develop an immune response that will control and eradicate the virus. But in a few cases in persists and causes damage to cells in the lining of the cervix, Over time some of these cells may eventually change into cancer cells. The current UK-wide cervical smear testis designed to pick up the carly stages of this process. So what isthe new vaccine that is being introduced? Itfallsinto the category of asubunit vaccine, and further into the sub-category of a recombinant subunit vaccine. It is made of the main proteins found on the outside of the virus. Using molecular cloning techniques (see BrovocicaL Sciences Review, Vol. 21, No. 3, pp. 2-6) the gene encoding each protein has been isolated and the protein coded by the gene produced as a recom: binant protein in cultured cells, Rather neatly, the coat proteins self-assemble into virus-like particles but of course they are not Infectious because they have no DNA inside them. The purified virus-like particles {fofin the vaccine. As we discussed above for this type of vaccine, It is given In combination with an adju- vant to boost the immune response. This stimulates the immune response by activating cells through pattern recognition receptors. The immunisation schedule requires three injections over the course of 6 months. ‘The reports so far are that 100% of those immunised make a good protective antibody response. Ethics always matter ‘The sexual health of people is always going to raise some degree of controversy. The HPV immunisation programme is no different. To be protected you must bbe vaccinated prior to exposure to the virus, hence the initial targeting of young females, who are at most risk from the potentially severe long-term effects of HPV infection. But HPV also infects men, so perhaps we suid eventually extend the immunisation programme We isniieme hepevtnce of Vie he population even further. Vaccination itself is a topic that has been hotly debated in recent years. In the case of the MMR vaccine, a public health scare in the late 1990s resulted ina drop in the number of children being immunised. In some parts of the UK only around 80% of eligible children were being immunised, To achieve an effective coverage of the whole population — an effect called herd immunity, where even non-immunised people are essentially protected — this rate needs to be closer to 95%. So itis no coincidence that in recent years in the UK we have seen increases of measles cases and a dramatic peak of mumps cases in 2005. Where next for vaccines? As we increase our knowledge of how the immune response works, we can try to manipulate the response gggencrate better vaccines. For example, targeting He Sinune cs tung specie pera SEPTEMBER 2009 recognition receptors may enhance their effective ness, or We could extract dendritic cells and load them with pathogen-derived proteins, then. re-injec into patients (see pp. 28-31). This latter approach is of particular interest to researchers wiho are trying to generate vaccines against cancers. In the case of the HPY vaccine that we have discussed here, although it has often been reported as a ‘vaccine against cancer’ if you think about it, it is actually a traditional vaccin that stops a viral infection, However, since that virus can eventually cause cancer, the net effect is to stop a cancer from forming, ‘A really huge step forward would come if we could vaccinate people against the many other types of cancer that occur. There is some hope of such an. immunisa tion programme working. Many cancer cells express new proteins or slightly altered proteins, Some of these can be recognised by the immune system, but too often the response is very weak. If we can find a way of helping the immune system 10 make a much stronger response against these cancer-specific proteins, then we would have an immensely strong weapon in the fight against cancer. 7 Things to do > Research what category the in the UK fll into: live attenuated, dead or subunit > Discuss what diseases you think we might be able to. vaccinate against in the future. Dr Simon Powis is 2 lecturer in immunology in the Medical School atthe University of St Andrews, His current research is focused on haw the immune system sometimes works against, rather than for, you, a process called autoimmunity. In particular, he is working on a type of autoimmune arthritis that can lead to painful fusion of vertabrae in the spine. KEY ins ‘© Vaccination relies on activating the immune system. ‘© Receptors on cells of the adeptive immune system recognise molecules carried by pathogens, «© Infection with structures such as weakened viruses ‘activates the immune system but does not cause disease — this is vaccination, ‘© The goal of most vaccines Is to produce @ strong antibody response in the blood that will stop invading pathogens from becoming established infections ‘© The current vaccination programme for children and teenagers in the UK protects from diseases, such as diphtheria, tetanus, whooping cough, polio, ‘measles, mumps, rubella, pneumococcal infection, rmeningtts C and now HPV infection ute